Cognition enhancing derivatives of isoxazole triazoloindane GABA-A alpha 5 receptor subunit ligands

ABSTRACT

The present invention relates to compounds of formula I:  
                 
 
     in which R 1  is a linear group or a five membered heterocycle optionally fused to a phenyl ring, R 2  is a 5-membered heterocycle, R 3  is chosen from a range of substituents, m is 0-3 and n is 0 or 1; the compounds are generally inverse agonists at GABA-A receptors containing the alpha 5 subunit and so are useful in methods of enhancing cognition in subjects with diminished cognition in diseases such as Alzheimer&#39;s Disease.

[0001] The present invention relates to a class of substituted isoxazoletriazoloindane derivatives and to their use in therapy. Moreparticularly, this invention is concerned with substituted isoxazoletriazoloindane derivatives which are ligands for GABAA receptorscontaining the α5 subunit and are therefore useful in therapy wherecognition enhancement is required.

[0002] Receptors for the major inhibitory neurotransmitter,gamma-aminobutyric acid (GABA), are divided into two main classes: (1)GABA_(A) receptors, which are members of the ligand gated ion channelsuperfamily; and (2) GABA_(B) receptors, which maybe members of theG-protein linked receptor superfamily. Since the first cDNAs encodingindividual GABA_(A) receptor subunits were cloned the number of knownmembers of the mammalian family has grown to thirteen (six (x subunits,three β subunits, three γ subunits and one δ subunit). It may be thatfurther subunits remain to be discovered; however, none has beenreported since 1993.

[0003] Although knowledge of the diversity of the GABA_(A) receptor genefamily represents a huge step forward in our understanding of thisligand-gated ion channel, insight into the extent of subtype diversityis still at an early stage. It has been indicated that an α subunit, a βsubunit and a γ subunit constitute the minimum requirement for forming afully functional GABA_(A) receptor expressed by transiently transfectingcDNAs into cells. As indicated above, a δ subunit also exists, but isapparently uncommon in the native receptor.

[0004] Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof thirteen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangementsof subunits around the ion channel had no constraints (i.e. there couldbe 120 possible variants for a receptor composed of five differentsubunits).

[0005] Receptor subtype assemblies which do exist include α1β2γ2,α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βγδ, α4βδ. Subtypeassemblies containing an α subunit are present in most areas of thebrain and account for over 40% of GABA_(A) receptors in the rat. Subtypeassemblies containing α2 and α3 subunits respectively account for about25% and 17% of GABA_(A) receptors in the rat. Subtype assembliescontaining an α5 subunit are primarily hippocampal and represent about4% of receptors in the rat.

[0006] A characteristic property of some GABA_(A) receptors is thepresence of a number of modulatory sites, of which the most explored isthe benzodiazepine (BZ) binding site through which anxiolytic drugs suchas diazepam and temazepam exert their effect. Before the cloning of theGABA_(A) receptor gene family, the benzodiazepine binding site washistorically subdivided into two subtypes, BZ1 and BZ2, on the basis ofradio ligand binding studies. The BZ1 subtype has been shown to bepharmacologically equivalent to a GABA_(A) receptor comprising the α1subunit in combination with β2 and γ2. This is the most abundantGABA_(A) receptor subtype, representing almost half of all GABA_(A)receptors in the brain.

[0007] A number of dementing illnesses such as Alzheimer's disease arecharacterised by a progressive deterioration in cognition in thesufferer. It would clearly be desirable to enhance cognition in subjectsdesirous of such treatment, for example for subjects suffering from adementing illness.

[0008] It has been reported by McNamara and Skelton in Psychobiology,21:101-108 that benzodiazepine receptor inverse agonist, β-CCM enhancedspatial learning in the Morris watermaze. However, β—CCM and otherconventional benzodiazepine agonists are proconvulsant, which makes itclear that they cannot be used as cognition enhancing agents in humans.

[0009] However, we have now discovered that it is possible to obtainmedicaments which have cognition enhancing effects which may be employedwith less risk of proconvulsant effects previously described withbenzodiazepine receptor partial or full inverse agonists.

[0010] It has now been discovered that an α5 receptor partial or fullinverse agonist, which is relatively free of activity at α1 and/or α2and/or α3 receptor binding sites, can be used to provide a medicamentwhich is useful for enhancing cognition but in which proconvulsantactivity is reduced or eliminated. Inverse agonists at α5 which are notfree of activity at α1 and/or α2 and/or α3 but which are functionallyselective for α5 can also be used. Inverse agonists which are bothselective for α5 and are relatively free of activity at α, α2 and α3receptor binding sites are preferred.

[0011] WO-A-9850385 discloses substituted1,2,4-triazolo[3,4-a]pyridazines which are GABA_(A) receptor ligandsselective for the α5 binding sites.

[0012] WO-A-9917769 discloses substituted indeno[1,2-c]-,naphtho[1,2-c]- and benzo[6,7]cyclohepta[1,2-c]pyrazoles as tyrosinekinase inhibitors.

[0013] The present invention provides compounds of formula I:

[0014] in which:

[0015] R¹ is (i) hydrogen, halogen, cyano, amino, nitro, hydroxy,aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,aminoC₁₋₆alkyl or C₁₋₆alkylcarbonyl each of which is unsubstituted orsubstituted by one, two or three halogen atoms;

[0016] (ii) a 5-membered heterocyclic ring containing 1, 2, 3 or 4heteroatoms independently selected from O, N or S, at most one beingoxygen or sulphur, or a 6-membered aromatic ring optionally containing 1or 2 nitrogen heteroatoms, said rings being unsubstituted or substitutedby at least one halogen, hydroxy, COOH, cyano, NR^(a)R^(b),CONR^(a)R^(b), C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, C₁₋₆alkoxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl or C₁₋₆alkylcarbonyl, each of which is itselfunsubstituted or substituted by one, two or three halogen atoms; or

[0017] (iii) a 5-membered heterocyclic ring containing 1, 2, 3 or 4heteroatoms independently selected from O, N or S, at most one beingoxygen or sulphur, or a 6-membered aromatic ring optionally containing 1or 2 nitrogen heteroatoms, one of said rings being fused with a phenylring wherein the resulting ring system is unsubstituted or substitutedwith at least one group selected from halogen, cyano, amino, nitro,hydroxy, aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alknyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,aminoC₁₋₆alkyl or C₁₋₆alkylcarbonyl each of which is unsubstituted orsubstituted by one, two or three halogen atoms;

[0018] R² is a 5-membered heterocyclic ring containing 1, 2, 3 or 4heteroatoms independently selected from O, N or S, at most one beingoxygen or sulphur, or a 6-membered aromatic ring optionally containing 1or 2 nitrogen heteroatoms, which ring is unsubstituted or substitutedwith at least one group selected from halogen, cyano, amino, nitro,hydroxy, aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,aminoC₁₋₆alkyl or C₁₋₆alkylcarbonyl each of which is itselfunsubstituted or substituted by one, two or three halogen atoms;

[0019] R³ is hydrogen, halogen, cyano, armino, nitro, hydroxy,aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl or NR^(c)R^(d), each of which isunsubstituted or substituted by one, two or three halogen atoms;

[0020] R^(a) and R^(b) are each independently hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, aminoC₁₋₆alkyl or phenyl;

[0021] R^(c) and R^(d) are each independently hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted by a6-membered heterocyclic group containing 1 or 2 nitrogen atoms;

[0022] m is 0, 1, 2 or 3; and

[0023] n is O or 1;

[0024] and pharmaceutically acceptable salts thereof.

[0025] As used herein, the expression “C₁₋₆alkyl” includes methyl andethyl groups, and straight-chained and branched propyl, butyl, pentyland hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,isopropyl and t-butyl. Derived expressions such as “C₂₋₆alkenyl”,“C₂₋₆alkynyl”, “hydroxyC₁₋₆alkyl”, “C₁₋₆alkylcarbonyl”, and“aminoC₁₋₆alkyl” are to be construed in an analogous manner.

[0026] Unless otherwise specified, 5- and 6-membered heterocyclic ringscontaining 1, 2 or 3 nitrogen heteroatoms or 1 oxygen or 1 sulphurheteroatom shall include pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl,pyrrolyl, furyl, thienyl, pyiazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl and triazolylgroups. Suitable 6-membered heterocyclic rings containing 3 nitrogenatoms include 1,2,4-triazine and 1,3,5-triazine. A suitable heterocyclicring containing 4 nitrogen atoms is the tetrazole ring. When aheterocyclic ringcomprises a hydroxy group as a susbstituent, andketo-enol tautomerism is possible, both tautomers are included withinthe scope of the invention.

[0027] The expression “6-membered aromatic ring” will, unless otherwisespecified, include phenyl.

[0028] The term “halogen” as used herein included fluorine, chlorine,bromine and iodine.

[0029] As used herein the term “C₁₋₆alkoxy” includes methoxy and ethoxygroups, and straight-chained and branched propoxy, butoxy, pentoxy andhexoxy groups. Derived expressions such as “C₂₋₆alkenyloxy”,“C₂₋₆alkynyloxy” and “C₁₋₆alkoxyC₁₋₆alkyl” should be construed in ananalogous manner.

[0030] In the compounds of formula (I), R¹ is typically (i) hydrogen,halogen, hydroxy, cyano, nitro, C₁₋₄alkyl, C₁₋₄alkoxy or halogenatedC₁₋₄alkoxy; preferably hydrogen, brormo, nitro, cyano, hydroxy, methyl,methoxy or trifluoromethoxy; (ii) a phenyl group, a phenyl groupsubstituted by nitro, cyano, halogen, C₁₋₄alkyl or halogenatedC₁₋₄alkyl; a 5-membered heterocyclic group containing either one oxygenheteroatom, one sulphur heteroatom, from 1 to 3 nitrogen heteroatoms orone nitrogen and one sulphur or oxygen heteroatom, the heterocyclicgroup being either uusubstituted or substituted with, for example,nitro, C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; or a 6-membered heterocyclicgroup containing 1 or 2 nitrogen heteroatoms and being unsubstituted orsubstituted with halogen, NR^(a)R^(b), CONR^(a)R^(b), C₁₋₄alkyl,C₁₋₄alkoxy or halogenated C₁₋₄alkyl, wherein R^(a) and R^(b) are asdefined above. We generally prefer, under this definition that R¹ is aphenyl group, a phenyl group substituted with cyano, or a pyridine,pyrimidine, pyradizine, pyrazine, tetrahydropyridine, furan, thiazole ortriazole ring, the ring being unsubstituted or substituted by at leastone NR^(a)R^(b), CONR^(a)R^(b), methyl, cyano, COOH, methoxy orpyrazinyl group. In the third alternative, R¹ may be a 5- or 6-memberedheterocyclic ring fused with a phenyl ring. The resulting ring systemmay be unsubstituted or substituted by a variety of substitutents. Ofthese substituents we generally prefer the C₁₋₄alkyl or halogenatedC₁₋₄alkyl and most prefer the trifluoromethyl substituent. The ringsystem itself is typically composed of a phenyl ring fused with either afuryl ring, a thienyl ring or a pyridine ring.

[0031] In the compounds of the present invention, R² is generally aphenyl ring, a 5-membered heterocyclic ring or a 6-membered heterocyclicring as hereinabove defined. These rings may be unsubstituted orsubstituted by a variety of substituents. We generally prefer that R²represents a phenyl ring, either unsubstituted or substituted,preferably unsubstituted. When substituted this is preferably by ahalogen atom and is most preferably the 4-fluorophenyl group.

[0032] The present invention provides compounds of formula (I) in whichR³ may be a variety of substituents. We generally prefer that R³represents a halogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, halogenated C₁₋₄alkylor NR^(c)R^(d) group, in which R^(c) and R^(d) are as defined above,more preferably a halogen, C₁₋₂alkyl, hydroxyC₁₋₂alkyl, halogenatedC₁₋₂alkyl or NHR^(d) group, in which R^(d) is as defined above, and mostpreferably a chloro, methyl, hydroxymethyl, fluoromethyl or

[0033] In a preferred embodiment of the present invention we providecompounds of formula (I), as shown above, in which:

[0034] n represents 0 and R¹ represents hydrogen, cyano, amino, bromo,methyl, methoxy, phenyl, cyanophenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, thiazolyl, furyl, tetrahydropyridin-4-yl,methylpyridazinyl, methoxypyridazinyl, aminopyridazinyl,2-amino-3-methylpyridyl, aminocarbonylpyridinyl, methylpyrazinyl,carboxypyrazinyl, 4-methyl-3,4,5,6-tetrahyrdo2H-[1,2′]bipyrazinyl-6yl,dimethoxypyrimidinyl orN,N,N′-trimethyl-N′-pyridazin-3-ylethane-1,2-diamine; or

[0035] n represents 1, m represents 2 and R¹ represents pyridinyl;

[0036] R² represents phenyl or fluorophenyl;

[0037] R³ represents chloro, methyl, hydroxymethyl, fluoromethyl or

[0038] and pharmaceutically acceptable salts thereof.

[0039] Representative of the present invention are the followingcompounds:

[0040]3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0041]8-methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0042]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1H-[1,2,4]tri4zol-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0043]8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0044]6-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0045]8-(4,5-dihydro-1H-imidazol-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0046]3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyridin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0047]3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-5-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0048]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methyl-pyridazin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0049]3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0050]3-(5-methyl-3-phenylisoxazol-4-yl)-8-thiazol-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0051]3-methyl-5-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylamine;

[0052]5-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-nicotinamide;

[0053]8-isothiazol-5-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0054]3-(5-methyl-3-phenylisoxazol-4-yl)-8-thiazol-4-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0055]3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrazin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0056]8-(2,6-dimethoxypyrimidin-4-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0057]8-(6-methoxypyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0058]8-furan-3-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0059]6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-pyridazin-3-ylamine;

[0060]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0061]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0062]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyrazin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0063]methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}amine;

[0064]N,N,N′-trimethyl-N′-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}ethane-1,2-diamine;

[0065]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0066]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0067]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(5-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0068]methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-yl}amine;

[0069]dimethyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine;

[0070]methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine;

[0071]N,N′-trimethyl-N′-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}ethane-1,2-diamine;

[0072]3-(5-methyl-3-phenylisoxazol-4-yl)-9-(pyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0073]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(pyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0074]3-[3-(5-methyl-3-phenylisoxazol-4-yl-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-benzonitrile;

[0075]8-methyl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0076]3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole-8-carbonitrile;

[0077]8-bromo-3-(5-hydroxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0078]8-bromo-3-(5-chloro-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0079]8-bromo-3-(5-[2-aminomethylpyridinyl)-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0080]3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ylamine;

[0081]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(pyridin-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0082]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(pyridin-2-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0083]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0084]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0085]6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyrazme-2-carboxylicacid

[0086]8-bromo-3-(5-fluoromethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;and

[0087]3-(5-methyl-3-phenylisoxazol-4-yl)-8-(pyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;

[0088] and pharmaceutically acceptable salts thereof.

[0089] Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess one or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the present invention.

[0090] For use in medicine, the compounds of formula (I) may be in theform of pharmaceutically acceptable salts. Hence in a favoured aspectthis invention provides the compounds of formula (I) in the form ofpharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts and salts formed withsuitable organic ligands, e.g. quaternary ammonium salts.

[0091] The compounds of the present invention have a good bindingaffinity (Ki) for the α5 subunit of the GABA_(A) receptor. In apreferred embodiment the compounds of the present invention are bindingselective for the α5 subunit relative to the α1, α2 and α3 subunits. Inanother preferred embodiment the compounds are functionally selectivefor the α5 subunit as partial or full inverse agonists whilstsubstantially being antagonists at the α1, α2 and α3 subunits.Particularly preferred are compounds which are both binding andfunctionally selective.

[0092] The invention also provides pharmaceutical compositionscomprising one or more compounds of this invention and apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage form, such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, transdermal patches, auto-injectordevices or suppositories; for oral, parenteral, intranasal, sublingualor rectal administration, or for administration by inhalation orunsufflation. For preparing solid compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients, such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums or surfactants, such as sorbitan monooleate,polyethylene glycol and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. When referring to these preformulations as homogeneous, itis meant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms, such as tablets, pills andcapsules. This solid preformulation composition is then subdivided intounit dosage forms of the type described above containing from 0.1 toabout 500 mg of the active ingredient of the present invention. Typicalunit dosage forms contain from 1 to 100 mg, for example, 1, 2, 5, 10,25, 50 or 100 mg, of the active ingredient. The tablets or pills of thenovel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

[0093] The present invention also provides a compound of the inventionfor use in a method of treatment in the human body. Preferably thetreatment is for a condition associated with GABA_(A) receptorscomprising the α5 subunit and/or for enhancement of cognition.Preferably the condition is a neurological deficit with an associatedcognitive disorder such as a dementing illness such as Alzheimer'sdisease. Other conditions to be treated include cognition deficits dueto traumatic injury, stroke, Parkinson's disease, Downs syndrome, agerelated memory deficits, attention deficit disorder and the like.

[0094] The present invention further provides the use of a compound ofthe present invention in the manufacture of a medicament for theenhancement of cognition, preferably in a human being suffering from adementing illness such as Alzheimer's disease.

[0095] Also disclosed is a method of treatment of a subject sufferingfrom a cognition deficit, such as that resulting from a dementingillness such as Alzheimer's disease, which comprises administering tothat subject an effective amount of a compound according to the presentinvention.

[0096] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums, suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0097] For the enhancement of cognition, a suitable dosage level isabout 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg perday and especially about 0.01 to 5 mg/kg of body weight per day. Thecompounds may be administered on a regimen of 1 to 4 times per day. Insome cases, however, dosage outside these limits may be used.

[0098] The present invention also provides a process for the preparationof a compound of formula I, as defined above, which comprises reacting acompound of formula II:

[0099] in which R¹, m and n are as defined above, with a compound offormula III:

[0100] in which R² and R³ are as defined above and are optionallyprotected. The reaction is typically carried out by formation of ahydrazone in the presence of an inert organic solvent, such asdichloromethane and in the presence of an acid such as 10%trifluoroacetic acid followed by oxidative cyclisation with bromine. Ifnecessary deprotection of the product to achieve the compound of formulaI is carried out.

[0101] The compound of formula II is produced by reacting a compound offormula IV with hydrazine:

[0102] wherein R¹, m and n are as defined above, generally in a solventsuch as THF in the presence of a base such as triethylamine.

[0103] The compound of formula IV is prepared by reacting a compound offormula V with methyl trifluoromethanesulfonate:

[0104] wherein R¹, m and n are as defined above, generally in a solventsuch as dichloromethane for about an hour.

[0105] Where not commercially available, the compound of formula V canbe prepared by reacting a compound of formula VI with ammonia:

[0106] wherein R¹, m and n are as defined above, generally in a mixtureof solvents such as THF/methanol. The compounds of formula VI can bemade by bromination of the appropriate derivative of methyl2-methylbenzoate by reacting with a brominating agent such as N-bromosuccinimide at reflux in carbon tetrachloride. The starting material iscommercially available or can be made from commercially availablecompounds by known methods.

[0107] Alternatively, a compound of formula V may be prepared byreacting a compound of formula XIII with N-hydroxyphthalimide:

[0108] wherein R¹, m and n are defined above, generally in concentratedsulfuric acid for about 3 hours at about 80° C. Compounds of formulaXIII are commercially available or may be made by known methods fromcommercially available compounds.

[0109] The compound of formula III can be prepared by reacting acompound of formula VII with a mild oxidizing agent such as Dess-Martinperiodinane:

[0110] wherein R and R³ are as defined above, generally in a solventsuch as dichlomethane in the presence of a base such as pyridine at roomtemperature for about 30 minutes.

[0111] The compound of formula VII can be produced by reducing acompound of formula VIII with a reagent such as diusobutyl aluminiumhydride:

[0112] wherein R² and R³ are as defined above, generally in a solventsuch as toluene at about −78° C. for about 1.5 hours.

[0113] The compound of formula VIII can be prepared by reacting acompound of formula IX with a compound of formula X:

[0114] wherein R² and R³ are as defined above, generally in a water-freesolvent such as anhydrous methanol in the presence of a strong base suchas sodium methoxide for several hours. Where they are not commerciallyavailable, the compounds of formulae IX and X can be made fromcommercially available compounds by known methods.

[0115] In an alternative embodiment, compounds of formula I can beproduced by cyclizing a compound of formula XI:

[0116] wherein R¹, R², R³, m and n are as defined above, generally in asolvent such as toluene in the presence of acid such as acetic acid atreflux for about 16 hours.

[0117] The compound of formula XI can be produced by reacting a compoundof formula IV with a compound of formula XII:

[0118] wherein R² and R³ are as defined above, generally in the presenceof a base such as triethylamine and with heating at reflux for about 16hours, optionally with the portionwise addition of the compound offormula XII and further heating at reflux for a further 16 hours.Compounds of formula XII are commercially available or can be preparedfrom commercially available compounds by known methods.

[0119] Compounds of formula I may also be produced by interconversionfrom other compounds of formula I as illustrated in the Examples.

[0120] It will also be appreciated that where more than one isomer canbe obtained from a reaction then the resulting mixture of isomers can beseparated by conventional means.

[0121] Where the above described process for the preparation ofcompounds according to the invention gives rise to mixtures ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The novel compounds may be preparedin racemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-d-tartaricacid, followed by fractional crystallisation and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

[0122] During any of the above synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0123] The following non-limiting Examples serve to illustrate thepresent invention.

EXAMPLE 13-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0124] a) 3-Methoxy-1H-isoindolium trifluoromethanesulfonate

[0125] 1H-Isoindolone (5 g, 38 mmol) in dichloromethane (100 ml) wasstirred with methyl trifluoromethanesulfonate (6.38 ml, 56 mmol) for onehour. The solvent was removed and the residue was triturated with etherand dried to yield product. (9.5 g, 86%). ¹H NMR (360 MHz, d6 DMSO) δ7.97 (1H, d, J=7.2 Hz), 7.90-7.83 (2H,m), 7.67 (1H, t, J=7.2 Hz), 5.04(2H, s), 4.38 (3H, s), m/z (ES⁺) 148 (M⁺).

[0126] b) 5-Methyl-3-phenylisoxazole-4-carboxylic acidN′-(3H-isoindol-1-yl)hydrazide

[0127] To a solution of 3-methoxy-1H-isoindoliumtrifluoromethanesulfonate (1 g, 3.4 mmol) in ethanol (40 ml) was added5-methyl-3-phenyl-4-isoxazoyl hydrazide (0.878 g, 4.04 mmol) andtriethylamine (0.7 ml, 5.05 mmol). After heating to reflux for sixteenhours another portion of 5-methyl-3-phenyl-4-isoxazoyl hydrazide (0.878g, 4.04 mmol) was added and the reaction was heated to reflux for afurther sixteen hours. The reaction was cooled and the resultingprecipitate was filtered to give product as a yellow solid. (0.875 g,78%). ¹H NMR (360 MHz, d6 DMSO) δ 10.18 (1H, s), 7.75-7.28 (10H, in),4.55 (2H, s), 2.56 (3H, s), m/z (ES⁺) 333 (M+H)⁺.

[0128] c)3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0129] 5-Methyl-3-phenylisoxazole-4-carboxylic acidN′-(3H-isoindol-1-yl)hydrazide (0.1 g, 0.31 mmol) was suspended intoluene (20 ml) and acetic acid (0.4 ml) was added. The reaction washeated to reflux for 16 hours and the solvent was removed and theresidue was dissolved in dichloromethane and washed with water. Theorganic layer was dried, filtered and evaporated to yield a residuewhich was purified by column chromatography on silica using isohexaneand ethyl acetate (1:1) to yield the title compound (26 mg, 27%), ¹H NMR(500 MHz, CDCl₃) δ 8.01 (1H, d, J=7.5 Hz), 7.55-7.39 (7H, m), 7.27 (1H,d, J=7.5 Hz), 4.02 (2H, s), 2.70 (3H,s), m/z (ES⁺) 315 (M+H)⁺.

EXAMPLE 28-Methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0130] a) 3,5-Dimethoxy-1H-isoindolium trifluoromethanesulfonate

[0131] Prepared in a similar manner to that of Example 1a using6-methoxy-2,3-dihydro isoindol-1-one (Daiichi Yakka Daigaku Kenkyu Nenpo1989, 20, 1-10.)

[0132]¹H NMR (400 MHz, d6 DMSO) δ 7.73 (1H, d, J=8 Hz), 7.45 (1H, d, J=8Hz), 7.45 (1H, s), 4.98 (2H, s), 3.95 (3H, s) m/z (ES⁺) 178 (M)⁺.

[0133] b)8-Methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0134] 3,5-Dimethoxy-1H-isoindolium trifluoromethanesulfonate (3.2 g,9.8 mmol) in ethanol (50 ml) with triethylamine (0.99 g, 9.8 mmol) wasstirred with hydrazine hydrate for one hour, the reaction mixture wasevaporated and azeotroped with dry toluene. The residue was dissolved in10% trifluoroacetic acid in dichloromethane and5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (1.87 g, 10 mmol)and the reaction was stirred for 0.5 hours. The solvent was removed andthe residue was partitioned between ethyl acetate and water and theorganic layer was washed with saturated sodium hydrogen carbonate,dried, filtered and evaporated. The residue was taken up into methanol(50 ml), sodium acetate was added and the stirred suspension was treateddropwise with bromine (0.5 ml). The reaction was diluted with water andextracted into dichloromethane and dried, filtered and evaporated. Theproduct was purified by silica chromatography using ethyl acetate aseluant to yield the title compound (1.1 g, 32%). ¹H NMR (360 MHz, d6DMSO) δ 7.52-7.41 (7H, m), 7.04 (1H, dd, J=2.4, 8.4 Hz), 4.44 (2H, s),3.85 (3H, s), 2.60 (3H, s), m/z (ES⁺) 345 (M+H)⁺.

EXAMPLE 3 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1H-r1,2,4]triazol-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0135] a)3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol

[0136]8-Methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(4.6 g, 13 mmol) in dichloromethane (70 ml) was stirred with borontribronide (25 g) for five days. The reaction was cooled to −78° C. anddiethyl ether was added dropwise followed by water. The reaction waswarmed to room temperature and the organic layer was washed with waterand dried, filtered and evaporated. The residue was purified by columnchromatography on silica using methanol/dichloromethane to yield thetitle compound.

[0137]¹H NMR (360 MHz, d6 DMSO) δ 10.10 (1H, brs), 7.52-7.44 (5H, m),7.33 (1H, d, J=7.2 Hz), 7.25 (1H, d, J=2 Hz), 6.90 (1H, dd, J=7.2, J=2Hz), 4.43 (2H, s), 2.6 (3H, s), m/z (ES⁺) 331 (M+H)⁺.

[0138] b)3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl[1,2,4]triazol-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0139]3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol(35 mg) and potassium carbonate (30 mg) and5-(chloromethyl)-2-methyltriazole were heated together with DMF (1 ml)at 120° C. for 2 hours. The reaction was diluted with water andextracted with ethyl acetate. The organic layer was washed with water(x5), dried and evaporated to yield an oil which was purified by columnchromatography on silica using methanol/dichloromethane to yield thetitle compound (7.8 mg).

[0140]¹H NMR (360 MHz, d6 DMSO) δ 8.05 (1H, s), 7.67 (1H, d, J=2 Hz,7.53-7.38 (5H, m), 7.18-7.07 (2H, m), 5.21 (2H, s), 3.96 (2H, s), 3.94(3H, s), 2.70 (3H, s). m/z (ES⁺) 426 (M+H)⁺.

EXAMPLE 48-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0141] a) 6-Bromo-2,3-dihydroisoindol-1-one

[0142] Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved inTHF/methanol (200 ml) (1:1) and the solution obtained was saturated withdry ammonia gas. The solvent was removed and the residue was trituratedwith water, diethyl ether and hexane and then recrystallised fromethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one(12.5 g). ¹H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77(1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES⁺) 212 (M⁺).

[0143] b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate

[0144] Prepared in a similar manner to that of Example 1a using6-bromo-2,3-dihydro-isoindol-1-one. ¹H NMR (360 MHz, CDCl₃) δ 12.5 (1H,brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd,J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES⁺) 226 (M⁺).

[0145] c) (6-Bromo-3H-isoindol-1-yl)hydrazine

[0146] 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was addedfollowed by hydrazine (1 M in THF, 35 ml). After an hour the solid whichhad precipitated was filter off and dried to give title compound (2.8 g)¹H NMR (360 MHz, CDCl₃) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H,dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 arrd 1 Hz), 4.49 (2H,s). m/z (ES⁺)226 (M⁺).

[0147] d)8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0148] (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10%trifluoroacetic acid in dichloromethane (40 ml) and5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and thereaction was stirred for 0.5 hours. The solvent was removed and theresidue was partitioned between ethyl acetate and water and the organiclayer was washed with saturated sodium hydrogen carbonate, dried,filtered and evaporated. The residue was taken up into methanol anddichloromethane, sodium acetate was added and the stirred suspension wastreated dropwise with bromine (0.5 ml). The reaction was diluted withwater and extracted into dichloromethane and dried, filtered andevaporated. The product was purified by silica chromatography usingethyl acetate as eluant to yield the title compound (1.46 g).

[0149]¹H NMR (400 MHz, d6 DMSO) δ 8.13 (1H,d, J=1 Hz), 7.68 (1H, dd, J=7and 1 Hz), 7.53-7.43 (6H, m), 4.54 (2H, s), 2.60 (3H, s). m/z (ES⁺) 394(M⁺).

EXAMPLE 56-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0150] Prepared in a similar manner to Example 4 using4-bromo-2,3-dihydro-isoindol-1-one,

[0151]¹H NMR (400 MHz, d6 DMSO) δ 7.97 (1H,d, J=7 Hz), 7.72(1H, d, J=7),7.55-7.45 (6H,m), 4.47 (2H, s), 2.63 (3H, s). m/z (ES⁺) 394 (M⁺).

EXAMPLE 68-(4,5-Dihydro-1H-imidazol-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)—SH-[1,2,4]triazolo[3,4-a]isoindole

[0152] a) 6-Iodo-2,3-dihydroisoindol-1-one

[0153] 3-Iodobenzoic acid (50 g, 0.2 mol) and N-hydroxymethylphthalimide(35.7 g, 0.2 mol) were suspended in concentrated sulfuric acid (200 ml)and heated for three hours at 80° C. The reaction mixture was pouredonto ice and the product was filtered, washed with water and diluteammonium hydroxide and then stirred in hot (70° C.) ethanol for 1.5hours before cooling and drying to yield the title compound (24 g, 45%).¹H NMR (360 MHz, d6 DMSO) X 8.63 (1H, brs), 7.95 (1H, s), 7.92 (1H, d,J=7 and 1 Hz), 7.42 (1H, d, J=7 and 1 Hz), 4.33 (2H, s). m/z (ES⁺) 260(M⁺).

[0154] b) 5-Iodo-3-methoxy-1H-isoindolium trifluoromethanesulfonate

[0155] Prepared in a similar manner to that of Example 1a using6-iodo-2,3-dihydro-isoindol-1-one. ¹H NMR (360 MHz, CDCl₃) δ 12.5 (1H,brs), 8.26 (1H,d, J=1 Hz), 8.14 (1H, dd, J=7 and 1 Hz), 7.53 (1H, d, J=7Hz), 5.06 (2H, s), 4.58 (3H, s). m/z (ES⁺) 274 (M⁺).

[0156] c) 5-Methyl-3-phenylisoxazole-4-carboxylic acidNA-(6-iodo-3H-isoindol-1-yl)-hydrazide

[0157] Prepared in a similar manner to that of Example 1b using5-Iodo-3-methoxy-1H-isoindolium trifluoromethanesulfonate

[0158] d)8-Iodo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0159] 5-Methyl-3-phenylisoxazole-4-carboxylic acidN′-(6-iodo-3H-isoindol-1-yl)-hydrazide (19.96 g) was heated in aceticacid (200 ml) at reflux for five hours. The reaction was cooled andevaporated. The residue was purified by column chromatography on silicausing 40% ethyl acetate/isohexane to yield8-iodo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]-triazolo[3,4-a]isoindole(5.6 g). ¹H NMR (360 MHz, CDCl₃) 7.72 (1H,d, J=1 Hz), 7.53-7.34 (6H,m),7.01 (1H, d, J=7 Hz) 3.93 (2H, s), 2.71 (3H, s). m/z (ES⁺) 441 (M⁺).

[0160] e)3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole-8-carboxylicAcid Methyl Ester

[0161]8-Iodo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(3.1 g), triethylamine (6 ml) andtetrakis(triphenylphosphine)palladium(0) (0.5 g) were suspended in adegassed mixture of 1,4-dioxane (50 ml) and methanol (100 ml). Thereaction was heated to 75° C. and a slow stream of carbon monoxide waspassed through the reaction mixture for 16 hours. The reaction wasevaporated and purified by column chromatography on silica to yield thetitle compound (1.9 g). ¹H NMR (360 MHz, CDCl₃) 8.46 (1H, s), 7.83 (1H,d, J=7 Hz), 7.45-7.37 (5H, m), 7.24 (1H, d, J=7 Hz), 4.01(2H, s), 3.79(3H, s), 2.71(3H, s). m/z (ESt) 373 (M⁺).

[0162] f) 8(2-Imidazolinyl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0163] Ethylenediamine (160 mg) in toluene (5 ml) was cooled to 5° C.and trimethylaluminium (2 M in toluene, 1 ml) was added. The reactionmixture was allowed to warm to 25° C. and then3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole-8-carboxylicacid methyl ester (200 mg) was added and the reaction mixture was heatedto reflux for 2 hours. The reaction was cooled, methanol was added andthe reaction was evaporated and the residue was purified by columnchromatography on silica to yield the title compound afterrecrystallisation from ethyl acetate (80 mg). ¹H NMR (360 MHz, d6 DMSO)δ 8.32 (1H, s), 7.96 (1H, dd, J=7 and 1 Hz), 7.56-7.41 (6H, m), 4.59(2H, s), 3.66 (3H, s), 2.59 (3H, s). m/z (ES⁺) 383(M⁺).

EXAMPLE 73-(5-Methyl-3-phenylisoxazol-4-yl)-8-pyridin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0164] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(290 mg) prepared as in Example 4), bis(pinacolato)diboron (226 mg),KOAc (218 mg) and dioxane (10 ml) was degassed with a stream of N₂ for0.5h. Bis(triphenylphosphine)palladium(11) chloride (5 mg) was added andthe reaction heated to 80° C. for 4 h. The reaction was cooled,2-bromopyridine (0.14 ml), Cs₂CO₃ (1.2 g/2 ml H₂O), andbis(triphenylphosphine)palladium(II) chloride (14 mg) were added andheated at 80° C. for 3 days. The reaction mixture was cooled, pouredinto H₂O and extracted into CH₂Cl₂, dried (MgSO₄), and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica, eluting with 1.5% MeOH/CH₂Cl₂, andrecrystallised from CH₂Cl₂hexane to give the title compound (20 mg, 7%).¹H NMR (500 MHz, CDCl₃) δ 8.73 (1H, d, J=4.5 Hz), 8.58 (1H, s), 8.16(1H, d, J=7.5 Hz), 7.84-7.79 (2H, m), 7.56-7.55 (2H, m), 7.49-7.29 (5H,m), 4.07 (2H, s), 2.73 (3H, s), m/z (ES⁺) 392 (M+H)⁺.

EXAMPLE 83-(5-Methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-5-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0165] Prepared in a similar manner to Example 7 using 5-bromopyrimidineto give the title compound (60 mg, 40%). ¹H NMR (400 MHz, CDCl₃) δ 9.27(1H, s), 9.00 (2H, s), 8.24 (1H, s), 7.63-7.40 (7H, m), 4.08 (2H, s),2.73 (3H, s), m/z (ES⁺) 393 (M+H)⁺.

EXAMPLE 93-(5-Methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyridazin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0166] Prepared in a similar manner to Example 7 using3-chloro-6-methylpyridazine to give the title compound (75 mg, 61%). ¹HNMR (400 MHz, CDCl₃) δ 8.54 (1H, d, J=1.2 Hz), 8.33 (1H, dd, J=9.7, 1.6Hz), 7.83 (1H, d, J=8.7 Hz), 7.57-7.40 (7H, m), 4.08 (2H, s), 2.80 (3H,s), 2.73 (3H, s), m/z (ES⁺) 407 (M+H)⁺.

EXAMPLE 103-(5-Methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0167] Prepared in a similar manner to Example 7 using 2-bromopyrimidineto give the title compound (14 mg, 12%). ¹H NMR (500 MHz, CDCl₃) δ 9.15(1H, s), 8.85 (2H, s), 8.53 (1H, dd, J=8, 1.5 Hz), 7.56 (2H, dd, J=2.5,1 Hz), 7.49-7.37 (4H, m), 7.27-7.25 (1H, m), 4.08 (2H, s), 2.73 (3H, s),m/z (ES⁺) 393 (M+H)⁺.

EXAMPLE 113-(5-Methyl-3-phenylisoxazol-4-yl)-8-thiazol-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0168] Prepared in a similar manner to Example 7 using 2-bromothiazoleto give the title compound (8 mg, 7%). ¹H NMR (400 MHz, CDCl₃) δ 8.56(1H, d, J=1.2 Hz), 8.09 (1H, dd, J=8.1, 1.6 Hz), 7.91 (1H, d, J=3.2 Hz),7.56-7.54 (2H, m), 7.48-7.34 (5H, m), 4.05 (2H, s), 2.72 (3H, s), m/z(ES⁺) 398 (M+H)⁺.

EXAMPLE 123-Methyl-5-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-pyridin-2-ylamine

[0169] Prepared in a similar manner to Example 7 using2-amino-5-bromo-3-methylpyridine to give the title compound (30 mg,24%). ¹H NMR (360 MHz, CDCl₃) δ 8.22 (1H, d, J=2.2 Hz), 8.15 (1H, d,J=1.3 Hz), 7.56-7.53 (4H, m), 7.49-7.39 (3H, m), 7.30 (1H, d, J=8.1 Hz),4.04 (2H, s), 2.72 (3H, s), 2.23 (3H, s), m/z (ES⁺) 421 (M+H)⁺.

EXAMPLE 135-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-nicotinamide

[0170] Prepared in a similar manner to Example 7 using3-bromonicotinamide to give the title compound (34 mg, 26%). ¹H NMR (360MHz, CDCl₃) δ 9.05 (2H, d, J=2.0 Hz), 8.44 (1H, t, J=2.2), 8.29 (1H, s),7.68 (1H, dd, J=8.1, 1.7 Hz), 7.55 (2H, dd, J=6.6, 4.3 Hz), 7.51-7.41(4H, m), 4.08 (2H, s), 2.73 (3H, s), m/z (ES⁺) 435 (M+H)⁺.

EXAMPLE 148-Isothiazol-5-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0171] Prepared in a similar manner to Example 7 using5-bromoisothiazole to give the title compound (55 mg, 46%). ¹H NMR (400MHz, CDCl₃) δ 8.52 (1H, d, J=1.8 Hz), 8.27 (1H, d, J=1.4), 7.64 (1H, dd,J=7.9, 1.6 Hz), 7.56-7.53 (2H, m), 7.50-7.35 (5H, m), 4.05 (2H, s), 2.73(3H, s), m/z (ES⁺) 398 (M+H)⁺.

EXAMPLE 153-(5-Methyl-3-phenylisoxazol-4-yl)-8-thiazol-4-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0172] Prepared in a similar manner to Example 7 using 4-bromothiazole(Synthesis, 1986, 9, 757-60) to give the title compound (50 mg, 42%). ¹HNMR (400 MHz, CDCl₃) δ 8.92 (1H, s), 8.52 (1H, d, J=1.1 Hz), 8.08 (1H,dd, J=8.0, 1.6 Hz), 7.67 (1H, d, J=1.9 Hz), 7.57-7.54 (2H, m), 7.47-7.40(3H, m), 7.35 (1H, dd, J=8.2, 0.6 Hz), 4.05 (2H, s), 2.72 (3H, s), m/z(ES⁺) 398 (M+H)⁺.

EXAMPLE 163-(5-Methyl-3-phenylisoxazol-4-yl)-8-pyrazin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole

[0173] Prepared in a similar manner to Example 7 using chloropyrazine togive the title compound (25 mg, 25%). ¹H NMR (360 MHz, CDCl₃) δ 9.10(1H, d, J=1.5 Hz), 8.68-8.67 (2H, m), 8.58 (1H, d, J=2.4 Hz), 8.12 (1H,dd, J=8.1, 1.6 Hz), 7.57-7.54 (2H, m), 7.48-7.40 (4H, m), 4.08 (2H, s),2.73 (3H, s), m/z (ES⁺) 393 (M+H)⁺.

EXAMPLE 178-(2,6-Dimethoxypyrimidin-4-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0174] Prepared in a similar manner to Example 7 using6-chloro-2,4-dimethoxypyrimidine to give the title compound (19 mg,14%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (1H, d, J=1.2 Hz), 8.12 (1H, dd,J=8.1, 1.7 Hz), 7.56-7.36 (6H, m), 6.84 (1H, s), 4.11 (3H, s), 4.06 (2H,s), 4.04 (3H, s), 2.73 (3H, s), m/z (ES⁺) 453 (M+H)⁺.

EXAMPLE 188-(6-Methoxypyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0175] Prepared in a similar manner to Example 7 using3-chloro-6-methoxypyridazine to give the title compound (9 mg, 8%). ¹HNMR (360 MHz, CDCl₃) δ 8.50 (1H, s), 8.26 (1H, dd, J=8.1, 1.5 Hz), 7.85(1H, d, J=9.2 Hz), 7.56-7.40 (6H, m), 7.12 (1H, d, J=9.3 Hz), 4.21 (3H,s), 4.08 (2H, s), 2.73 (3H, s), m/z (ES⁺) 423 (M+H)⁺.

EXAMPLE 198-Furan-3-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0176] Prepared in a similar manner to Example 7 using 3-bromofuran togive the title compound (11 mg, 10%). ¹H NMR (400 MHz, CDCl₃) δ 8.13(1H, d, J=1.2 Hz), 7.81 (1H, s), 7.56-7.39 (6H, in), 7.28-7.26 (2H, in),6.75-6.74 (1H, m), 4.03 (2H, s), 2.72 (3H, s), m/z (ES⁺) 381 (M+H)⁺.

EXAMPLE 206-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-pyridazin-3-ylamine

[0177] Prepared in a similar manner to Example 7 using3-amino-6-chloropyridazine to give the title compound (34 mg, 28%). ¹HNMR (400 MHz, CDCl₃) δ 8.42 (1H, d, J=1.0 Hz), 8.17-8.20 (1H, m), 7.77(1H, d, J=9.2 Hz), 7.54-7.39 (6H, m), 6.94 (1H, d, J=9.2 Hz), 4.09 (2H,s), 2.72 (3H, s), m/z (ES⁺) 408 (M+H)⁺.

EXAMPLE 213-(5-Methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0178] Prepared in a similar manner to Example 7 using4-bromo-2-methylpyridine (Rocz. Chem., 1968, 42(12), 2061-76) to givethe title compound (18 mg, 15%). ¹H NMR (360 MHz, CDCl₃) δ 8.60 (1H, d,J=5.2 Hz), 8.28 (1H, s), 7.66 (1H, d, J=6.9 Hz), 7.55 (2H, d, J=6.9 Hz),7.48-7.34 (6H, m), 4.07 (2H, s), 2.73 (3H, s), 2.66 (3H, s), m/z (ES⁺)406 (M+H)⁺.

EXAMPLE 223-(5-Methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0179] Prepared in a similar manner to Example 7 using3-bromo-2-methylpyridine (Bull. Soc. Chim. Fr., 1972, 6, 2466-81) togive the title compound (23 mg, 19%). ¹H NMR (400 MHz, CDCl₃) δ 8.56(1H, dd, J=4.8, 1.7 Hz), 7.98 (1H, s), 7.58-7.41 (6H, m), 7.36 (2H, d,J=1.3 Hz), 7.26-7.22 (1H, m), 4.08 (2H, s), 2.72 (3H, s), 2.52 (3H, s),m/z (ES⁺) 406 (M+H)⁺.

EXAMPLE 233-(5-Methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyrazin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0180] Prepared in a similar manner to Example 7 using2-chloro-6-methylpyrazine (Tetrahedron, 1972, 28(15), 4155-70) to givethe title compound. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (1H, s), 8.70 (1H,s), 8.46 (1H, s), 8.11 (1H, dd, J=8.0, 1.4 Hz), 7.56-7.39 (6H, m), 4.08(2H, s), 2.73 (3H, s), 2.66(3H, s), m/z (ES⁺) 407 (M+H)⁺.

EXAMPLE 24Methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-pyridazin-3-yl}-amine

[0181] a)8-(6-Chloropyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0182] Prepared in a similar manner to Example 7 using3-chloro-6-iodopyridazine (Tetrahedron, 1999, 55(52), 15067-15070) togive the title compound (190 mg, 25%).

[0183]¹H NMR (400 MHz, CDCl₃) δ 8.55 (1H, d, J=1.4 Hz), 8.31 (1H, dd,J=8.1, 1.6 Hz), 7.91 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=9.0 Hz),7.57-7.54 (2H, m), 7.48-7.40 (4H, m), 4.09 (2H, s), 2.73 (3H, s), m/z(ES⁺) 427 (M+H)⁺.

[0184] b)Methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}amine

[0185]8-(6-Chloropyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindolewas heated in a sealed tube with methylamine (3 ml of 40% solution inwater) for 16 h. The reaction mixture was cooled, poured into H₂O andextracted into CH₂Cl₂, dried (MgSO₄), and concentrated under reducedpressure. Purified on alumina prep plates eluting with 3% MeOH/CH₂Cl₂ togive the title compound (12 mg, 24%). ¹H NMR (360 MHz, CDCl₃) δ 8.42(1H, d, J=1.2 Hz), 8.25 (1H, dd, J=8.1, 1.6 Hz), 7.72 (1H, d, J=9.4 Hz),7.56-7.37 (6H, m), 6.82 (1H, d, J=9.4 Hz), 4.06 (2H, s), 3.10 (3H, s),2.72 (3H, s), m/z (ES⁺) 422 (M+H)⁺.

EXAMPLE 25N,N,N′-Trimethyl-N′-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}ethane-1,2-diamine

[0186] Prepared in a similar manner to Example 24 usingN,N,N′-trimethylethylene diamine to give the title compound (49 mg,43%). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (1H, d, J=1.3 Hz), 8.29 (1H, dd,J=8.2, 1.6 Hz), 7.69 (1H, d, J=9.5 Hz), 7.56-7.54 (2H, m), 7.47-7.35(4H, m), 6.91 (1H, d, J=9.6 Hz), 4.05 (2H, s), 3.48 (2H, t, J=7.0 Hz),3.22 (3H, s), 2.72 (3H, s), 2.62 (2H, t, J=7.1 Hz), 2.34 (6H, s), m/z(ES⁺) 493 (M+H)⁺.

EXAMPLE 263-(5-Methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0187] a)8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0188] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(290 mg) (prepared as in Example 4), bis(neopentyl glycolato)diboron(201 mg), KOAc (218 mg) and dioxane (5 ml) was degassed with a stream ofN₂ for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (5 mg) wasadded and the reaction heated to 90° C. for 2 h. The reaction mixturewas cooled, poured into H₂O and extracted into EtOAc, dried (MgSO₄), andconcentrated under reduced pressure and was used without furtherpurification in the next step.

[0189] b)3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(6-methyl-pyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0190] A mixture of8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(315 mg), 2-bromo-6-methylpyridine (0.34 ml), Cs₂CO₃ (1 g/l ml H₂O), anddioxane (10 ml) was degassed with a stream of N₂ for 0.5 h.Bis(triphenylphosphine)palladium(II) chloride (15 mg) was added andheated at reflux for 2 h. The reaction mixture was cooled, poured intoH₂O and extracted into CH₂Cl₂, dried (MgSO₄), and concentrated underreduced pressure. The residue was purified by column chromatography onsilica, eluting with 1.5% MeOH/CH₂Cl₂, and recrystallised fromCH₂Cl₂/hexane to give the title compound (78 mg, 26%). ¹H NMR (360 MHz,CDCl₃) δ 8.60 (1H, d, J=1.2 Hz), 8.12 (1H, dd, J=8.1, 1.5 Hz), 7.69 (1H,t, J=7.7 Hz), 7.59-7.54 (3H, m), 7.47-7.34 (4H, m), 7.16 (1H, d, J=7.6Hz), 4.06 (2H, s), 2.73 (3H, s), 2.64 (3H, s), m/z (ES⁺) 406 (M+H)⁺.

EXAMPLE 273-(5-Methyl-3-phenylisoxazol-4-yl)-8-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0191] Prepared in a similar manner to Example 26 using2-chloro-6-(4′-methylpiperazin-1-yl) pyrazine hydrochloride (DE 2617205)to give the title compound (40 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 8.69(1H, s), 8.37 (1H, s), 8.14 (1H, s), 8.01 (1H, dd, J=8.2, 1.6 Hz),7.56-7.54 (2H, m), 7.49-7.39 (3H, m), 7.35 (1H, d, J=8.3 Hz), 4.07 (2H,s), 3.75 (4H, t, J=5.0 Hz), 2.73 (3H, s), 2.58 (4H, t, J=5.2 Hz), 2.39(3H, s), m/z (ES⁺) 491 (M+H)⁺.

EXAMPLE 283-(5-Methyl-3-phenylisoxazol-4-yl)-8-(5-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0192] Prepared in a similar manner to Example 26 using2-bromo-5-methylpyridine to give the title compound (33 mg, 35%). ¹H NMR(400 MHz, CDCl₃) δ 8.55-8.54 (2H, m), 8.13 (1H, dd, J=8.1, 1.6 Hz), 7.69(1H, d, J=8.0 Hz), 7.63-7.61 (1H, m), 7.56-7.54 (2H, m), 7.47-7.34 (4H,m), 4.06 (2H, s), 2.72 (3H, s), 2.40 (3H, s).

EXAMPLE 29Methyl-{6-[3-(-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-yl}amine

[0193] a)8-(6-Bromopyridin-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0194] Prepared in a similar manner to Example 26 using2,6-dibromopyridine to give the title compound (480 mg, 44%). ¹H NMR(400 MHz, CDCl₃) δ 8.57 (1H, d, J=1.3 Hz), 8.16 (1H, dd, J=8.2, 1.8 Hz),7.77-7.75 (1H, m), 7.68-7.64 (1H, m), 7.56-7.54 (2H, m), 7.49-7.36 (5H,m), 4.06 (2H, s), 2.73 (3H, s).

[0195] b)Methyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-yl}amine

[0196] Prepared from8-(6-bromopyridin-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindolein a similar manner to Example 24(b) to give the title compound (7 mg,8%). ¹H NMR (400 MHz, CDCl₃) δ 8.63 (1H, d, J=1.3 Hz), 8.07 (1H, dd,J=8.0, 1.6 Hz), 7.56-7.38 (6H, m), 7.31 (1H, d, J=8.4 Hz), 7.07 (1H, d,J=7.3 Hz), 6.41 (1H, d, J=8.2 Hz), 4.64 (1H, brs), 4.05 (2H, s), 3.01(3H, d, J=4.3 Hz), 2.72 (3H, s), m/z (ES⁺) 421 (M+H)⁺.

EXAMPLE 30Dimethyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine

[0197] a) 2-Bromo-6-bromomethyl-pyridine

[0198] A mixture of 2-bromo-6-methylpyridine (5.7 ml), NBS (8.9 g) andbenzoyl peroxide (50 mg) in CCl₄ (50 ml) were heated to reflux for 16 h.The reaction was filtered and the solution obtained was used withoutfurther purification in the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.56(1H, t, J=7.8 Hz), 7.45-7.40 (1H, m), 7.28 (1H, d, J=8.2 Hz), 4.50 (2H,s).

[0199] b) (6-Bromopyridin-2-ylmethyl)dimethylamine

[0200] 2-Bromo-6-bromomethyl-pyridine and NHMe₂ (10 ml of 2M solution inTHF) were reacted at RT for 16 h. The reaction mixture was poured intoH₂O, extracted into CH₂Cl₂ and the concentrated residue purified bycolumn chromatography on silica, eluting with 1% MeOH/CH₂Cl₂ to give thetitle compound (440 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (1H, t, J=7.6Hz), 7.40 (1H, d, J=7.5 Hz), 7.36 (1H, d, J=7.8 Hz), 3.57 (2H, s), 2.29(6H, s).

[0201] c)Dimethyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine

[0202] Prepared in a similar manner to Example 26 using(6-bromopyridin-2-ylmethyl)-dimethylamine to give the title compound (40mg, 39%). ¹H NMR (360 MHz, CDCl₃) δ 8.63 (1H, d, J=1.1 Hz), 8.13 (1H,dd, J=8.1, 1.5 Hz), 7.78 (1H, t, J=7.7 Hz), 7.67 (1H, d, J=7.7 Hz),7.56-7.54 (2H, m), 7.47-7.34 (5H, m), 4.06 (2H, s), 3.70 (2H, s), 2.73(3H, s), 2.37 (6H, s), m/z (ES⁺) 449 (M+H)⁺.

EXAMPLE 31Methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine

[0203] a) (6-Bromopyridin-2-ylmethyl)methylamine

[0204] Prepared in a similar manner to Example 30(b) using NH₂Me (50 mlof 40% solution in water) to give the title compound (260 mg). ¹H NMR(400 MHz, d6 DMSO) δ 9.09 (1H, s), 7.87 (1H, t, J=7.8 Hz), 7.71 (1H, d,J=7.8 Hz), 7.58 (2H, d, J=7.7 Hz), 4.31 (2H, s), 2.63 (3H, s).

[0205] b)Methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}amine

[0206] Prepared in a similar manner to Example 26 using(6-bromopyridin-2-ylmethyl)-methylamine to give the title compound (15mg, 15%). ¹H NMR (400 MHz, CDCl₃) δ 8.66 (1H, d, J=1.2 Hz), 8.13 (1H,dd, J=8, 1.6 Hz), 7.77 (1H, t, J=7.8 Hz), 7.67 (1H, d, J=7.7 Hz),7.56-7.34 (6H, m), 7.30 (1H, d, J=7.5 Hz), 4.07 (2H, s), 3.97 (2H, s),2.73 (3H, s), 2.57 (3H, s), m/z (ES⁺) 435 (M+H)⁺.

EXAMPLE 32N,N,N′-Trimethyl-N′-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}ethane-1,2-diamine

[0207] a)N-(6-Bromopyridin-2-ylmethyl)-N,N′,N′-trimethylethane-1,2-diamine

[0208] Prepared in a similar manner to Example 30(b) usingN,N,N′-trimethylethylenediamine (2.5 ml) to give the title compound (250mg). ¹H NMR (360 MHz, CDCl₃) δ 7.52 (1H, t, J=7.6 Hz), 7.46 (1H, d,J=6.9 Hz), 7.35 (1H, d, J=7.6 Hz), 3.68 (2H, s), 2.58-2.55 (2H, m),2.46-2.42 (2H, m), 2.30 (3H, s), 2.23 (6H, s).

[0209] b)N,N,N′-Trimethyl-N-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylmethyl}ethane-1,2-diamine

[0210] Prepared in a similar manner to Example 26 usingN-(6-Bromopyridin-2-ylmethyl)-N,N′,N′-trimethylethane-1,2-diamine togive the title compound (6 mg, 5%).

[0211]¹H NMR (400 MHz, CD₃OD) δ 8.62 (1H, d, J=1.3 Hz), 8.17 (1H, dd,J=8.1, 1.6 Hz), 7.94-7.86 (2H, m), 7.56-7.44 (7H, m), 4.41 (2H, s), 3.85(2H, s), 3.35-3.28 (4H, m), 2.66 (3H, s), 2.47 (6H, s), 2.40 (3H, s),m/z (ES⁺) 506 (M+H)⁺.

EXAMPLE 333-(5-Methyl-3-phenylisoxazol-4-yl)-9-(pyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0212] Prepared in a similar manner to Example 7 from3-(5-methyl-3-phenylisoxazol-4-yl)-9-bromo-5H-[1,2,4]triazolo[3,4-a]isoindole(100 mg) (prepared using 7-bromo-2,3-dihydroisoindol-1-one by analogywith Example 4) and 3-bromopyridine (0.06 ml) to give the title compound(7 mg, 3%). ¹H NMR (360 MHz, CDCl₃) δ 8.90 (1H, s), 8.71 (1H, s), 8.40(1H, d, J=5.8 Hz), 7.56-7.40 (8H, m), 7.30 (1H, d, J-7.3 Hz), 4.08 (2H,s), 2.68 (3H, s), miz (ES⁺) 392 (M+H)⁺.

EXAMPLE 343-(5-Methyl-3-phenylisoxazol-4-yl)-8-(pyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0213] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(220 mg) (prepared as in Example 4), 4-pyridylboranic acid (295 mg),Cs₂CO₃ (1.26 g/l ml H₂O), and DME (3 ml) was degassed with a stream ofN₂ for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (42 mg) wasadded and the reaction heated to 100° C. for 5 h. The reaction mixturewas cooled, poured into H₂O and extracted into CH₂Cl₂, dried (MgSO₄),and concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica, eluting with 3% MeOH/CH₂Cl₂, andrecrystallised from CH₂Cl₂/hexane to give the title compound (50 mg,21%). ¹H NMR (360 MHz, CDCl₃) δ 8.72 (2H, d, J=4.5 Hz), 8.29 (1H, d,J=1.3 Hz), 7.67 (1H, dd, J=8.0, 1.7 Hz), 7.57-7.53 (4H, m), 7.48-7.39(4H, m), 4.07 (2H, s), 2.73 (3H, s), m/z (ES⁺) 392 (M+H)⁺.

EXAMPLE 353-[3-(5-Methyl-3-phenylisoxazol-4-yl-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-benzonitrile

[0214] Prepared in a similar manner to Example 34 using3-cyanophenylboronic acid to give the title compound (80 mg, 63%). ¹HNMR (400 MHz, CDCl₃) δ 8.22 (1H, s), 7.79-7.89 (2H, m), 7.71-7.59 (3H,m), 7.50-7.38 (6H, m), 4.07 (2H, s), 2.73 (3H, s), m/z (ES⁺) 416 (M+H)⁺.

EXAMPLE 368-Methyl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0215] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(100 mg) (prepared as in Example 4), methylboronic acid (72 mg), K₃PO₄(276 mg), and dioxane (5 ml) was degassed with a stream of N₂ for 0.5 h.tetrakis(triphenylphosphine) palladium(0) (20 mg) was added and thereaction heated to 80° C. for 1 h. The reaction mixture was cooled,poured into H₂O and extracted into CH₂Cl₂, dried (MgSO₄), andconcentrated under reduced pressure to give the title compound (56 mg,57%). ¹H NMR (400 MHz, CDCl₃) δ 7.82 (1H, s), 8.54-7.52 (2H, m),7.47-7.37 (3H, m), 7.21 (1H, dd, J=7.8, 0.7 Hz), 7.14 (1H, d, J=8.0 Hz),3.98 (2H, s), 2.70 (3H, s), 2.45 (3H, s), m/z (ES⁺) 329 (M+H)⁺.

EXAMPLE 373-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole-8-carbonitrile

[0216] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(300 mg) (prepared as in Example 4), zinc cyanide (187 mg), and DMF (5ml) was degassed with a stream of N₂ for 0.5 h.Tetrakis(triphenylphosphine) palladium(0) (20 mg) was added and thereaction heated to 80° C. for 2 days. The reaction mixture was cooled,poured into 10% ammonium hydroxide solution and extracted into EtOAc,dried (MgSO₄), and concentrated under reduced pressure. The residue waspurified by column chromatography on silica, eluting with 50%EtOAc/hexane, and recrystallised from EtOAc/hexane to give the titlecompound (15 mg, 6%). ¹H NMR (360 MHz, CDCl₃) δ 8.28 (1H, s), 7.69 (1H,dd, J=8.0, 1.4 Hz), 7.54-7.50 (2H, m), 7.48-7.39 (4H, m), 4.05 (2H, s),2.73 (3H, s), m/z (ES⁺) 340 (M+H)⁺.

EXAMPLE 388-Bromo-3-(5-hydroxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0217] a) Methyl 5-methoxymethylene-3-[4-fluorophenyl]isoxazole4-carboxylate

[0218] Methyl 4-methoxyacetoacetate (24 ml) was added to a freshlyprepared solution of sodium methoxide (1.2 eq) in 150 ml anhydrousmethanol. The yellow solution was stirred for 30 minutes prior todropwise addition of a solution of 4-fluorophenylchlorooxime in 50 mlanhydrous methanol. The reaction was allowed to stand overnight,filtered to remove solids and quenched with 5N HCl. The reaction wasconcentrated and partitioned between CH₂Cl₂—H₂O. The organic phase wasdried (MgSO₄), concentrated and purified by dry flash chromatographyusing 5 then-10% EtOAc-isohexanes as eluent to give the title compoundas a yellow solid (36 g, 95%).

[0219]¹H NMR (400 MHz, CDCl₃) δ 7.66-7.62 (2H, m), 7.17-7.12 (2H, m),4.87 (2H, s), 3.80 (3H, s), 3.52 (3H, s).

[0220] b)4-Hydroxymethylene-5-methoxymethylene-3-[4-fluorophenyl]isoxazole

[0221] A suspension of methyl5-methoxymethylene-3-[4-fluorophenyl]isoxazole 4-carboxylate (30 g,0.113 mol) in 100 ml anhydrous toluene was cooled to −78° C. undernitrogen. Diusobutyl aluminium hydride (250 ml of 1.0 M solution intoluene) was added slowly and the reaction allowed to stir at −78° C.for 1.5 h. The reaction was quenched with methanol then partitionedbetween CH₂Cl₂—H₂O. The organic extracts were washed with brine, dried(MgSO₄), and concentrated to give the title compound as a yellow oil (14g). ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.75 (2H, m), 7.26-7.15 (2H, m), 4.67(2H, s), 4.61-4.60 (2H, m), 3.50 (3H, s).

[0222] c) 5-Methoxymethylene-3-[4-fluorophenyl]isoxazole4-carboxaldehyde

[0223] A suspension of Dess-Martin periodinane (8.26 g) in 50 ml CH₂Cl₂was stirred at room temperature with 3 ml pyridine to give a turbidreaction. A solution of4-hydroxymethylene-5-methoxymethylene-3-[4-fluorophenyl]isoxazole (4.2g, 17.7 mmol) in 50 ml CH₂Cl₂ was added dropwise over 5 minutes and thereaction stirred for 30 minutes. The reaction was quenched with 1:1NaHCO₃—NaHSO₃ and stirred for 1 h, extracted into CH₂Cl₂, washed withbrine, dried (MgSO₄), and concentrated. Purification by chromatographyusing 20% EtOAc-isohexanes as eluent gave the title compound as acolourless solid (3.7 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ 10.07 (1H, s),7.77-7.73 (2H, m), 7.26-7.14 (2H, m), 4.90 (2H, s), 3.53 (3H, s).

[0224] d)8-Bromo-3-(5-methoxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0225] 5-Methoxymethylene-3-[4-fluorophenyl]isoxazole-4-carboxaldehyde(0.66 g) and (6-bromo-3H-isoindol-1-yl)hydrazine (0.64 g, 2.83 mmol)were reacted in a similar manner to that described in Example 4 to givethe title compound (0.6 g). m/z (ES⁺) 441/443 (M+H)⁺¹H NMR (400 MHz,d6-DMSO) δ 8.141-8.145 (1H, m), 7.703-7.708 (1H, m), 7.59-7.64 (3H, m),7.27 (2H, m), 4.73-4.74(4H, m), 3.32 (3H, s).

[0226] e)8-Bromo-3-(5-hydroxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0227] A solution of8-bromo-3-(5-methoxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(170 mg, 3.85 mmol) in 5 ml CH₂Cl₂ was cooled to −78° C. under anitrogen atmosphere. Boron tribromide (250 11) was added and thereaction allowed to attain room temperature. The reaction was re-cooledto 0° C. and quenched by addition of Et₂O followed by H₂O. The residuewas concentrated and purified using dry flash column chromatography andCH₂Cl₂ then 3% MeOH—CH₂Cl₂ as eluent. The title compound was obtainedafter crystallisation from ^(i)PrOH (135 mg, 82%). ¹H NMR (400 MHz,d6-DMSO) δ 8.13 (1H, s), 7.70-7.72 (1H, m), 7.57-7.64 (3H, m), 7.27-7.32(2H, m), 5.82 (1H, t, J=8.8 Hz), 4.80 (2Hf1 s), 4.73-4.75 (2H, d, J=8.8Hz). m/z (ES⁺) 427/429 (M+H)⁺.

EXAMPLE 398-Bromo-3-(5-chloro-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0228] 5-Chloro-3-phenylisoxazole 4-carboxaldehyde (1.1 g) and(6-bromo-3H-isoindol-1-yl)hydrazine (1.2 g, 5.3 mmol) were reacted in asimilar manner to that described in Example 4 to give the title compound(415 mg, 19%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.161-8.165 (1H, m),7.71-7.74 (1H, m), 7.47-7.61 (6H, m), 4.83 (2H, s).

EXAMPLE 408-Bromo-3-(5-[2-aminomethylpyridinyl)-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0229]8-Bromo-3-(5-chloro-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindolc(50 mg, 0.12 mmol) (prepared in Example 39), sodium acetate (30 mg) and2-(aminomethyl)pyridine (13 mg) in 5 ml methanol were heated to refluxfor 18 h. The reaction was cooled, concentrated and partitioned betweenH₂O—CH₂Cl₂. The organic phase and extracts were combined, dried over(MgSO₄) and concentrated. The residue was purified by preparative TLCusing 3% MeOH—CH₂Cl₂ as eluent. Trituration with ¹PrOH gave the titlecompound as a beige solid (11 mg). ¹H NMR (400 MHz, d6-DMSO) δ 8.53-8.54(1H, m), 8.38-8.40 (1H, m), 8.1 (1H, s), 7.75-7.8 (1H, m), 7.65-7.68(1H, m), 7.55-7.60 (2H, m), 7.38-7.5 (4H, m), 7.28-7.30 (2H, m),4.68-4.7 (2H, m), 4.45 (2H, s). m/z (ES⁺) 485/487 (M+H)⁺.

EXAMPLE 413-(5-Methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ylamine

[0230] a)1-(3-Phenyl-5-methyl-4-isoxazoloyl)-2-p-toluenesulfonylhydrazine

[0231] 3-Phenyl-5-methyl-4-isoxazoyl hydrazide (40 g, 0.184 mol)(prepared as in Example 1) was dissolved in anhydrous pyridine (300 ml)and cooled to 0° C. p-Toluenesulfonyl chloride (35.15 g, 0.184 mol) wasdissolved in anhydrous pyridine (200 ml) and added dropwise to thecooled hydrazide solution. The reaction was stirred for an additional 15minutes at 0° C., warmed to 25° C., and the pyridine removed in vacuo.The residue was poured into 30% HCl and the product extracted intoEtOAc. The organic layer was dried over MgSO₄ and evaporated. Theresidue was recrystallised from 70% EtOH to obtain the title compound asa beige solid (65 g, 95%). ¹H NMR (360 MHz, CDCl₃) δ 7.75 (2H, d, J=2.2Hz), 7.57-7.48 (5H, m), 7.29 (2H, d, J=2.2 Hz), 2.49 (3H, s), 2.43 (3H,s).

[0232] b)4-(4-Methylphenylsulfonyl)hydrazono(chloro)methyl-5-methyl-3-phenylisoxazole

[0233] 1-(3-phenyl-5-methyl-4-isoxazoloyl)-2-p-toluenesulfonylhydrazine(65 g, 0.175 mol) was placed in a flask containing thionyl chloride (300ml) and the reaction heated to reflux under nitrogen for 2 h. Thereaction mixture was cooled, the solvent removed in vacuo, and ethanoladded to the residue. The resulting solid was filtered, washed withethanol and dried in vacuo at 25° C. to obtain the title compound as awhite solid (60 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 8.25 (1H, s),7.76-7.73 (2H, m), 7.46-7.29 (7H, m), 2.45 (3H, s), 2.42 (3H, s).

[0234] c) 6-Nitro-2,3-dihydro-isoindol-1-one

[0235] To a solution of 2,3-dihydroisoindole-1-one (5 g, 38 mmol) inconcentrated sulfuric acid (100 ml) at 0° C., KNO₃ was added portionwisewhilst maintaining the temperature at 0° C. The reaction was graduallyallowed to warm to room temperature and was stirred overnight. Thereaction mixture was poured into ice and the resulting precipitate wasfiltered off and dried to give title compound as a yellow solid (4.7 g,70%). ¹H NMR (360 MHz, d6 DMSO) δ 8.96 (1H, s), 8.45 (1H, dd, J=8.3 Hz,2.2 Hz), 8.34 (1H, d, J=2 Hz), 7.87 (1H, d, J=8.3 Hz), 4.54 (2H, s). m/z(ES⁺) 179 (M⁺).

[0236] d) 6-Amino-2,3-dihydro-isoindol-1-one

[0237] 6-Nitro-2,3-dihydroisoindol-1-one (4.7 g, 26 mmol) was dissolvedin acetic acid (130 ml) and hydrogenated at 50 psi (3 bar) in thepresence of palladium on charcoal (0.47 g) overnight. The catalyst wasfiltered off through a pad of Hyflo™ and the acetic acid was removed invacuo. The residue was triturated with dichloromethane/hexane and theresulting solid was filtered off to afford the title compound (3.56 g,91%). ¹H NMR (360 MHz, d6 DMSO) X 8.28 (1H, s), 7.17 (1H, d, J=8 Hz),6.82 (1H, s), 6.78 (1H, dd, J=8.1, 1.8 Hz), 5.25 (2H, s), 4.16 (2H, s).m/z (ES⁺) 149 (M+H)⁺.

[0238] e) (3-Oxo-2,3-dihydro-1H-isoindol-5-yl)carbamic Acid Tert-ButylEster

[0239] To a solution of 6-amino-2,3-dihydroisoindol-1-one (1.78 g, 12mmol) in DMF/H₂O (2:1, 75 ml) was added K₂CO₃ (3.32 g, 24 mmol, 2 eq.)and di-tert-butyl dicarbonate (5.67 g, 26 mmol, 2.2 eq.). The reactionwas stirred at room temperature overnight. The reaction was partitionedbetween ethyl acetate and water, and the organic layer was washed withsaturated NaCl (aq), dried (MgSO₄), filtered and concentrated in vacuo.The residue was triturated with ethyl acetate and the resulting solidwas filtered off to afford title compound (2.04 g, 68%). ¹H NMR (360MHz, d6 DMSO) δ 8.48 (1H, s), 7.83 (1H, d, J=1.2 Hz), 7.6 (1H, dd,J=8.2, 1.9 Hz), 7.43 (1H, d, J=8.2 Hz), 4.28 (2H, s), 1.49 (9H, s).

[0240] f) 5-tert-Butoxycarbonylamino-3-methoxy-1H-isoindoliumtrifluoromethane sulfonate

[0241] Under nitrogen atmosphere,(3-oxo-2,3-dihydro-1H-isoindol-5-yl)-carbamic acid tert-butyl ester(2.14 g, 8.23 mmol) was dissolved in dichloromethane (190 ml) and methyltriflate (1.40 ml, 12 mmol, 1.5 eq.) was added. The reaction was heatedto reflux for 3 hours and then stirred at room temperature overnight.The reaction mixture was evaporated to one fifth of the original volumefollowed by the addition of diethyl ether. The resulting whiteprecipitate was filtered off to afford the title compound title compound(2.71 g, 80%). ¹H NMR (360 MHz, d6 DMSO) δ 9.87 (1H, s), 8.11 (1H, s),7.75 (1H, d,J=1.9 Hz), 7.70 (1H, d,J=8.4 Hz), 4.93 (2H, s), 4.35 (3H,s), 1.50 (9H, s).

[0242] g)3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ylamine

[0243] To a solution of5-tert-butoxycarbonylamino-3-methoxy-1H-isoindolium trifluoromethanesulfonate (0.53 g, 1.29 mmol) in 1,4-dioxane was addedN-p-toluenesulfonyl)-5-methyl-3-phenylisoxazol-4-hydrazidoyl chloride4-(4-methylphenylsulfonyl)hydrazono(chloro)methyl-5-methyl-3-phenylisoxazole(0.5 g, 1.29 mmol) and triethylamine (0.18 ml, 1.29 mmol). The reactionwas heated to reflux for one hour. The solvent was concentrated in vacuoand the residue was purified by silica chromatography, cluting with 2%methanol/dichloromethane. The resulting solid was dissolved intrifluoroacetic acid (5 ml) and was stirred at room temperature for 10minutes. The reaction was concentrated in vacuo and the residue waspartitioned between ethyl acetate and saturated K₂CO₃ (aq). The organiclayer was washed with saturated NaCl (aq), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silicachromatography, eluting with ethyl acetate 3% methanol/ethyl acetate, toafford the title compound title compound (97 mg, 23%). ¹H NMR (360 MHz,d6 DMSO) δ 7.53-7.44 (5H, m), 7.17 (1H, d, J=8.4 Hz), 7.14 (1H, s), 6.74(1H, d, J=7.9 Hz), 4.33 (2H, s), 2.59 (3H, s). m/z (ES⁺) 330 (M+H)⁺.

EXAMPLE 423-(5-Methyl-3-phenylisoxazol-4-yl)-8-(pyridin-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0244] Under nitrogen atmosphere, triphenylphosphine bound resin (0.41g, 0.45 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30minutes.3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol(0.1 g, 0.30 mmol) (prepared by Example 3 step (a)),3-hydroxymethylpyridine (44 μ1,0.45 mmol, 1.5 eq.) and diethylazodicarboxylate (71 μl, 0.45 mmol, 1.5 eq.) were added and the reactionwas stirred at room temperature overnight. The resin was filtered offand washed with dichloromethane, methanol and diethyl ether. Thecombined organics were concentrated in vacuo. The residue was purifiedfirstly by alumina chromatography, eluting with 1%methanol/dichloromethane, and secondly by silica chromatography, usingdichloromethane→5% methanol/dichloromethane as the eluant, to afford thetitle compound (21 mg, 16%). ¹H NMR (400 MHz, CDCl₃) δ 8.70-8.69 (1H,m), 8.61-8.59 (1H, m), 7.80 (1H, dt, J=7.8, 2.1 Hz), 7.59 (1H, d, J=2.4Hz), 7.54-7.52 (2H, m), 7.46-7.33 (4H, m), 7.18 (1H, d, J=8.4 Hz), 7.02(1H, dd, J=8.4, 2.4 Hz), 5.16 (2H, s), 3.96 (2H, s), 2.70 (3H, s). m/z(ES⁺) 422 (M+H)⁺.

EXAMPLE 433-(5-Methyl-3-phenylisoxazol-4-yl)-8-(pyridin-2-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0245] Prepared in a similar manner to Example 42 using2-hydroxymethylpyridine to yield the title compound (40 mg, 10%). ¹H NMR(400 MHz, CDCl₃) δ 8.62 (1H, dd, J=2.6, 2.3 Hz), 7.73 (1H, td, J=7.7,1.7 Hz), 7.60 (1H, d, J=2.4 Hz) 7.54-7.38 (6H, m), 7.25-7.24 (1H, m),7.16 (1H, d, J=8.6 Hz), 7.05 (1H, dd, J=8.5, 2.4 Hz), 5.27 (2H, s), 3.95(2H, s), 2.70 (3H, s). m/z (ES⁺) 422 (M+H)⁺.

EXAMPLE 443-(5-Methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0246] a)4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yloxy]-piperidine-1-carboxylicAcid Tert-Butyl Ester

[0247] Under nitrogen atmosphere, triphenylphosphine bound resin (1.22g, 1.36 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30minutes.3-(5:Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol(0.3 g, 0.91 mmol) (prepared as in Example 3, Step (a)),4-hydroxy-boc-piperidine (0.27 g, 1.36 mmol, 1.5 eq.) and diethylazodicarboxylate (0.21 ml, 1.36 mmol, 1.5 eq.) were added and thereaction was stirred at room temperature overnight. The resin wasfiltered off and washed with dichloromethane, methanol and ether. Thecombined organics were concentrated in vacuo. The residue was purifiedby alumina chromatography, eluting with dichloromethane 2%methanol/dichloromethane (0.5% methanol gradient), and was used withoutfurther purification in the next step.

[0248] b)3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0249]4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (466 mg, 0.91 mmol) was dissolved in TFA (5 ml)and stirred at room temperature for 1 hour. The reaction wasconcentrated in vacuo and the residue was partitioned between ethylacetate and saturated K₂CO₃ (aq). The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by aluminachromatography, eluting with dichloromethane o 5%methanol/dichloromethane (in 1% methanol gradient), to afford the titlecompound as a white solid (4 mg, 1% over 2 steps). ¹H NMR (400 MHz, d4MeOH) δ 7.53-7.43 (6H, m), 7.32 (1H, d, J=8.5 Hz), 7.08 (1H, dd, J=8.5,2.4 Hz), 4.63-4.60 (1H, m), 4.24 (2H, s), 3.16-3.11 (2H, m), 2.85-2.79(2H, m), 2.64 (3H, s), 2.09-2.05 (2H, m), 1.78-1.72 (2H, m). m/z (ES⁺)414 (M+H)⁺.

EXAMPLE 453-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0250] a) 4-Tributylstannyl-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester Prepared according to WO-A-0123381.

[0251] b)4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicAcid Tert-Butyl Ester

[0252]8-Iodo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(837 mg, 1.9 mmol) (as prepared in Example 6 Step (d)) and4-tributylstannyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (1.35 g, 2.85 mmol, 1.5 eq.) were dissolved in DMF (40 ml) anddegassed with nitrogen for one hour. Pd(PPh₃)₂Cl₂ (33 mg, 0.05 mmol) wasadded and the reaction was heated to 100° C. for 8 hours. The reactionwas partitioned between ethyl acetate and water. The organic layer waswashed with water (x3) and saturated NaCl (aq), dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by silicachromatography, eluting with 70% ethyl acetate/hexane ethyl acetate, toafford the title compound (750 mg, 80%). ¹H NMR (360 MHz, CDCl₃) δ 8.01(1H, s), 7.54-7.52 (2H, m), 7.46-7.40 (4H, m), 7.23 (1H, d, J=8.1 Hz),6.25-6.23 (1H, m), 4.13-4.11 (2H, m), 4.01 (2H, s), 3.66 (2H, t), 2.71(3H, s), 2.56-2.54 (2H, m), 1.50 (9H, s). m/z (ES⁺) 496 (M+H)⁺.

[0253] c)3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0254]4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (750 mg, 1.52 mmol) was dissolved in TFA (10 ml)and stirred at room temperature for 30 minutes. The reaction wasconcentrated in vacuo and the residue was partitioned between ethylacetate and saturated K₂CO₃ (aq). The organic layer was dried (MgSO₄),filtered, concentrated in vacuo. The residue was purified by aluminachromatography, using dichloromethane→5% methanol/dichloromethane (in 1%methanol gradient) as the eluant, to yield the title compound (460 mg,77%). ¹H NMR (360 MHz, CDCl₃) δ 8.02 (1H, d, J=1.04 Hz), 7.54-7.52 (2H,m), 7.47-7.38 (4H, m), 7.21 (1H, d, J=8.1 Hz), 6.23 (1H, t), 4.00 (2H,s), 3.59-3.58 (2H, m), 3.16 (2H, m), 2.71 (3H, s), 2.52-2.50 (2H, m).m/z (ES) 396 (M+H)⁺.

[0255] d)3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0256] Under nitrogen atmosphere,3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(50 mg, 0.13 mmol) was dissolved in methanol (2 ml) and formalinsolution (65 μl, 0.8 mmol) and sodium cyanoborohydride (32 mg, 0.52mmol) were added. The reaction was stirred at room temperature for 3hours. The reaction was concentrated in vacuo and partitioned betweenethyl acetate and water. The organic layer was washed with saturatedNaCl (aq), dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by alumina chromatography eluting withdichloromethane→2% methanol/dichloromethane (in 0.5% methanol gradient)to yield the title compound (21 mg, 41%). ¹H NMR (400 MHz, d4 McOH) δ8.01 (1H, d, J=1.3 Hz), 7.59 (1H, dd, J=1.6, 8.2 Hz), 7.52-7.42 (5H, m),7.40 (1H, d, J=8.2 Hz), 6.28-6.27 (1H m), 4.31 (2H, s), 3.21-3.20 (2H,m), 2.78 (2H, m), 2.69-2.66 (2H, m), 2.64 (3H, s), 2.43 (3H, s).

EXAMPLE 466-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyrazine-2-carboxylic Acid

[0257] A mixture of8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(248 mg, 0.58 mmol) (as prepared in Example 26 Step (a)), methyl6-chloropyrazine-2-carboxylate (100 mg, 0.58 mmol), dioxane (4.8 ml) and2M aqueous Cs₂CO₃ solution (0.58 ml) was degassed with a stream of N₂for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.22μmol) was added and the stirred mixture was heated at reflux for 1.5 h.The reaction was then cooled, allowed to stand for 15 min and thesupematent decanted off. The remaining salts were washed with furtherdioxane (5 ml) and then partitioned between water (20 ml) and CH₂Cl₂ (20ml). The pH was adjusted to 6 by dropwise addition of 2N aqueous HCl andthe aqueous phase was extracted with further CH₂Cl₂ (2×20 ml). Thecombined organic extracts were dried over Na₂SO₄ and concentrated invacuo to yield the title compound as a white amorphous solid (89.8 mg,34%); ¹H NMR (400 MHz, CDCl₃) δ 9.63 (1H, s), 9.19 (1H, s), 8.81 (1H,s), 8.38 (1H, dd, J=8.2, 1.7 Hz), 7.75 (1H, d, J=8.2 Hz), 7.56-7.48 (5H,m), 4.67 (2H, s), 2.64 (3H, s); m/z (ES⁺) 437 (M+H)⁺.

EXAMPLE 478-Bromo-3-(5-fluoromethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2;4]triazolo[3,4-a]isoindole

[0258] A suspension of8-bromo-3-(5-hydroxymethylenyl-3-[4-fluorophenyl]isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(93 mg, 0.21 mmol) (prepared as in Example 38) in 3 ml CH₂Cl₂ was cooledto −78° C. under a N₂ atmosphere. (Diethylaminosulphur) trifluoride (60mL) was added and the reaction allowed to warm to 0° C. after 20minutes. The reaction was poured into water, extracted, dried over MgSO₄and concentrated. The residue was purified by preparative tic using 1%MeOH—CH₂Cl₂ as eluent. The title compound was obtained as a solid (2mg). ¹H NMR (400 MHz, d6-DMSO) δ 8.14 (1H, s), 7.57-7.72 (4H, m),7.31-7.35 (2H, m), 7.75 (2H, m), 4.69 (2H, s). m/z (ES⁺) 429/431 (M+H)⁺.

EXAMPLE 483-(5-Methyl-3-phenylisoxazol-4-yl)-8-(pyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole

[0259] A mixture of8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole(100 mg) (as prepared in Example 4), 3-(tri-n-butylstannyl)pyridine (442mg) and DMF (5 ml) was degassed with a stream of N₂ for 0.5 h.Bis(triphenylphosphine)palladium(II) chloride (5 mg) was added and thereaction heated to 100° C. for 2 h. The mixture was concentrated underreduced pressure and the residue purified by column chromatography onsilica, eluting with 2.5% MeOH/CH₂Cl₂ to give the title compound (75 mg,64%). ¹H NMR (400 MHz, CDCl₃) δ 8.66 (1H, t, J=3.3 Hz), 8.23 (1H, d,J=1.4 Hz), 7.95-7.92 (1H, m), 7.63 (1H, dd, J=8.0, 1.7 Hz), 7.57-7.54(2H, m), 7.49-7.38 (5H, m), 4.07 (2H, s), 3.97 (2H, s), 2.73 IS (3H, s),m/z (ES⁺) 392 (M+H)⁺.

1. A compound of formula 1:

in which: R¹ is (i) hydrogen, halogen, cyano, amino, nitro, hydroxy,aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,aminoC₁₋₆alkyl or C₁₋₆alkylcarbonyl each of which is unsubstituted orsubstituted by one, two or three halogen atoms; (ii) a 5-memberedheterocyclic ring containing 1, 2, 3 or 4 heteroatoms independentlyselected from O, N or S, at most one being oxygen or sulphur, or a6-membered aromatic ring optionally containing 1 or 2 nitrogenheteroatoms, said rings being unsubstituted or substituted by at leastone halogen, hydroxy, COOH, cyano, NR^(a)R, CONR^(a)R^(b), C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂alkynyloxy,C₁₋₆alkoxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl orC₁₋₆alkylcarbonyl, each of which is itself unsubstituted or substitutedby one, two or three halogen atoms; or (iii) a 5-membered heterocyclicring containing 1, 2, 3 or 4 heteroatoms independently selected from O,N or S, at most one being oxygen or sulphur, or a 6-membered aromaticring optionally containing 1 or 2 nitrogen heteroatoms, one of saidrings being fused with a phenyl ring wherein the resulting ring systemis unsubstituted or substituted with at least one group selected fromhalogen, cyano, amino, nitro, hydroxy, aminocarbonyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂alkynyloxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl orC₁₋₆alkylcarbonyl each of which is unsubstituted or substituted by one,two or three halogen atoms; R² is a 5-membered heterocyclic ringcontaining 1, 2, 3 or 4 heteroatoms independently selected from O, N orS, at most one being oxygen or sulphur, or a 6-membered aromatic ringoptionally containing 1 or 2 nitrogen heteroatoms, which ring isunsubstituted or substituted with at least one group selected fromhalogen, cyano, amino, nitro, hydroxy, aminocarbonyl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂alkynyloxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl orC₁₋₆alkylcarbonyl each of which is itself unsubstituted or substitutedby one, two or three halogen atoms; R³ is hydrogen, halogen, cyano,amino, nitro, hydroxy, aminocarbonyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂alkynyloxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl or NR^(c)R^(d),each of which is unsubstituted or substituted by one, two or threehalogen atoms; R^(a) and R^(b) are each independently hydrogen,C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, aminoC₁₋₆alkyl orphenyl; R^(c) and R^(d) are each independently hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted by a6-membered heterocyclic group containing 1 or 2 nitrogen atoms; m is 0,1, 2 or 3; and n is O or 1; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 in which R¹ is (1) hydrogen, halogen,hydroxy, cyano, nitro, C₁₋₄alkyl, C₁₋₄alkoxy or halogenated C₁₋₄alkoxy;preferably hydrogen, bromo, nitro, cyano, hydroxy, methyl, methoxy ortrifluoromethoxy; (ii) a phenyl group, a phenyl group substituted bynitro, cyano, halogen, C₁₋₄alkyl or halogenated C₁₋₄alkyl; a 5-memberedheterocyclic group containing either one oxygen heteroatom, one sulphurheteroatom, from 1 to 3 nitrogen beteroatoms or one nitrogen and onesulphur or oxygen heteroatom, the heterocyclic group being eitherunsubstituted or substituted with, for example, nitro, C₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl; or a 6-membered heterocyclic group containing 1 or2 nitrogen heteroatoms and being unsubstituted or substituted withhalogen; NR^(a)R^(b), CONR^(a)R^(b), C₁₋₄alkyl, C₁₋₄alkoxy orhalogenated C₁₋₄alkyl, wherein R^(a) and R^(b) are as defined inclaim
 1. 3. A compound of claim 2 in which R² is a phenyl ring, eitherunsubstituted or substituted.
 4. A compound of claim 3 in which R³represents a halogen, C₁₋₄alkyl, hydroxy C₁₋₄alkyl, halogenated C₄alkylor NR^(c)R^(d) group, in which R^(c) and R^(d) are as defined inclaim
 1. 5. A compound of claim 1 in which: n represents 0 and R¹represents hydrogen, cyano, amino, bromo, methyl, methoxy, phenyl,cyanophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl,furyl, tetrahydropyridin-4-yl, methylpyridazinyl, methoxypyridazinyl,aminopyridazinyl, 2-amino-3-methylpyridyl, aminocarbonylpyridinyl,methylpyrazinyl, carboxypyrazinyl,4-methyl-3,4,5,6-tetrahyrdo2H-[1,2′]bipyrazinyl-6yl,dimethoxypyrimidinyl orN,N,N′-trimethyl-N′-pyridazin-3-ylethane-1,2-diamine; or n represents 1,m represents 2 and R¹ represents pyridinyl; R represents phenyl orfluorophenyl; R³ represents chloro, methyl, hydroxymethyl, fluoromethylor


6. A compound of claim 1 which is:3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;8-methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylsoxazol-4-yl)-8-(1-methyl-1H-[1,2,4]triazol-3-ylmethoxy)-5H-[1,2,4]triazolo[3,4-a]isoindole;8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;6-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;8-(4,5-dihydro-1H-imidazol-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)₅H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyridin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-5-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methyl-pyridazin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrimidin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-thiazol-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;3-methyl-5-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-ylamine;5-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-nicotinamide;8-isothiazol-5-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-thiazol-4-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-pyrazin-2-yl-5H-[1,2,4]triazolo[3,4-a]isoindole;8-(2,6-dimethoxypyrimidin-4-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;8-(6-methoxypyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;8-fiuran-3-yl-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]-pyridazin-3-ylamine;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(2-methylpyridin-3-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyrazin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}amine;N,N,N′-trimethyl-N′-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridazin-3-yl}ethane-1,2-diamine;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(6-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;3-(5-methyl-3-phenylisoxazol-4-yl)-8-(5-methylpyridin-2-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole;methyl-{6-[3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-yl]pyridin-2-yl}amine;or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition for enhancing cognition comprising an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 8. A method of treating a subjectwith diminished cognition which comprises administering to that subjecta therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 9. The method of claim 8 wherethe subject is suffering from Alzheimer's Disease.